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. 2022 Nov 8:11:e76143.
doi: 10.7554/eLife.76143.

New insights into anatomical connectivity along the anterior-posterior axis of the human hippocampus using in vivo quantitative fibre tracking

Marshall A Dalton  1   2   3 , Arkiev D'Souza  2   4   5 , Jinglei Lv  1   2 , Fernando Calamante  1   2   5
Affiliations

New insights into anatomical connectivity along the anterior-posterior axis of the human hippocampus using in vivo quantitative fibre tracking

Marshall A Dalton et al. Elife. .

Abstract

The hippocampus supports multiple cognitive functions including episodic memory. Recent work has highlighted functional differences along the anterior-posterior axis of the human hippocampus, but the neuroanatomical underpinnings of these differences remain unclear. We leveraged track-density imaging to systematically examine anatomical connectivity between the cortical mantle and the anterior-posterior axis of the in vivo human hippocampus. We first identified the most highly connected cortical areas and detailed the degree to which they preferentially connect along the anterior-posterior axis of the hippocampus. Then, using a tractography pipeline specifically tailored to measure the location and density of streamline endpoints within the hippocampus, we characterised where these cortical areas preferentially connect within the hippocampus. Our results provide new and detailed insights into how specific regions along the anterior-posterior axis of the hippocampus are associated with different cortical inputs/outputs and provide evidence that both gradients and circumscribed areas of dense extrinsic anatomical connectivity exist within the human hippocampus. These findings inform conceptual debates in the field and emphasise the importance of considering the hippocampus as a heterogeneous structure. Overall, our results represent a major advance in our ability to map the anatomical connectivity of the human hippocampus in vivo and inform our understanding of the neural architecture of hippocampal-dependent memory systems in the human brain.

Keywords: diffusion-weighted imaging; hippocampal subfields; hippocampus; human; neuroscience; structural connectivity; track-weighted imaging.

Plain language summary

The brain allows us to perceive and interact with our environment and to create and recall memories about our day-to-day lives. A sea-horse shaped structure in the brain, called the hippocampus, is critical for translating our perceptions into memories, and it does so in coordination with other brain regions. For example, different regions of the cerebral cortex (the outer layer of the brain) support different aspects of cognition, and pathways of information flow between the cerebral cortex and hippocampus underpin the healthy functioning of memory. Decades of research conducted into the brains of non-human primates show that specific regions of the cerebral cortex anatomically connect with different parts of the hippocampus to support this information flow. These insights form the foundation for existing theoretical models of how networks of neurons in the hippocampus and the cerebral cortex are connected. However, the human cerebral cortex has greatly expanded during our evolution, meaning that patterns of connectivity in the human brain may diverge from those in the brains of non-human primates. Deciphering human brain circuits in greater detail is crucial if we are to gain a better understanding of the structure and operation of the healthy human brain. However, obtaining comprehensive maps of anatomical connections between the hippocampus and cerebral cortex has been hampered by technical limitations. For example, magnetic resonance imaging (MRI), an approach that can be used to study the living human brain, suffers from insufficient image resolution. To overcome these issues, Dalton et al. used an imaging technique called diffusion weighted imaging which is used to study white matter pathways in the brain. They developed a tailored approach to create high-resolution maps showing how the hippocampus anatomically connects with the cerebral cortex in the healthy human brain. Dalton et al. produced detailed maps illustrating which areas of the cerebral cortex have high anatomical connectivity with the hippocampus and how different parts of the hippocampus preferentially connect to different neural circuits in the cortex. For example, the experiments demonstrate that highly connected areas in a cortical region called the temporal cortex connect to very specific, circumscribed regions within the hippocampus. These findings suggest that the hippocampus may consist of different neural circuits, each preferentially linked to defined areas of the cortex which are, in turn, associated with specific aspects of cognition. These observations further our knowledge of hippocampal-dependant memory circuits in the human brain and provide a foundation for the study of memory decline in aging and neurodegenerative diseases.

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Conflict of interest statement

MD, AD, JL No competing interests declared, FC is listed as one of the inventors in a patent awarded for the track-density imaging method

Figures

Figure 1.
Figure 1.. Twenty cortical brain areas with the highest degree of anatomical connectivity with the hippocampus.
(A) Histogram plotting the mean structural connectivity (n=10; given by the sum of SIFT2-weighted values) associated with the 20 cortical areas most strongly connected with the whole hippocampus (excluding medial temporal lobe [MTL] areas; see Figure 1—figure supplement 1 for MTL values). Error bars represent the standard error of the mean. (B) Histogram plotting the corresponding mean SIFT2-weighted values associated with anterior (yellow), body (red), and tail (blue) portions of the hippocampus for the 20 most strongly connected cortical areas presented in (A). Errors bars represent the standard error of the mean.
Figure 1—figure supplement 1.
Figure 1—figure supplement 1.. Medial temporal lobe (MTL) cortices anatomical connectivity with the hippocampus.
(A) Histogram plotting the mean structural connectivity (n=10; given by the sum of SIFT2-weighted values) associated with MTL cortical areas connected with the whole hippocampus. Error bars represent the standard error of the mean. (B) Histogram plotting the corresponding mean SIFT2-weighted values associated with anterior (yellow), body (red), and tail (blue) portions of the hippocampus for MTL cortical areas presented in (A). Errors bars represent the standard error of the mean.
Figure 2.
Figure 2.. Representative examples of the spatial distribution of endpoint density within the hippocampus for different cortical brain areas.
Representative examples of the location of endpoint densities associated with RSC in the medial parietal lobe (A), TGv in the temporal pole (B), and V1 in the occipital lobe (C). In each panel, the location of the relevant brain area is indicated in red on the brain map (left); a 3D-rendered representation of the bilateral group-level hippocampus mask is presented (middle; transparent grey) overlaid with the endpoint density map associated with each brain area (green); representative slices of the head, body, and tail of the hippocampus are displayed in the coronal plane (right; grey) and overlaid with endpoint density maps (white). Note that the spatial distribution of endpoint density within the hippocampus associated with each brain area differs along both the anterior–posterior and medial–lateral axes of the hippocampus. RSC and V1 displayed greatest endpoint density in the posterior medial hippocampus (yellow arrows in A, C). In contrast, TGv displayed greatest endpoint density in the anterior lateral hippocampus and in a circumscribed region in the anterior medial hippocampus (blue and white arrows, respectively, in B). Area V1 also expressed endpoint density in a circumscribed region in the anterior medial hippocampus (white arrows in C). A, anterior; P, posterior; M, medial; L, lateral.
Figure 2—figure supplement 1.
Figure 2—figure supplement 1.. Representative examples of the spatial distribution of endpoint density within the hippocampus for medial temporal lobe (MTL) brain areas.
Representative examples of the location of endpoint densities associated with EC (A), PeEc (B), PHA1 (C), PHA2 (D), and PHA3 (E). In each panel, the location of the relevant brain area is indicated in red on the brain map (top); a 3D-rendered representation of the bilateral group-level hippocampus mask (middle; transparent grey) is presented overlaid with the endpoint density map associated with each brain area (green); representative slices of the head, body, and tail of the hippocampus are displayed in the coronal plane (bottom; grey) and overlaid with endpoint density maps (white). Note that, as expected, the spatial distribution of endpoint density associated with MTL cortical areas is denser than that observed for non-MTL cortical areas (compare with Figure 2—figure supplements 2–4). EC displayed high endpoint density throughout the hippocampus (A). PeEc (B) and PHA3 (E) displayed the greatest endpoint density along the anterior–posterior extent of the lateral hippocampus (blue arrows) and in a circumscribed region in the anterior medial hippocampus (white arrows). PeEc and PHA3 showed little endpoint density in the posterior medial hippocampus. PHA1 (C) and PHA2 (D) displayed high endpoint density along the anterior–posterior extent of the lateral hippocampus (blue arrows), in the anterior medial hippocampus (white arrows) and, in contrast to PeEc and PHA3, in the posterior medial hippocampus (yellow arrows). A, anterior; P, posterior; M, medial; L, lateral.
Figure 2—figure supplement 2.
Figure 2—figure supplement 2.. Representative examples of the spatial distribution of endpoint density within the hippocampus associated with the five most highly connected medial parietal brain areas.
Representative examples of the location of endpoint densities associated with ProS (A), POS1 (B), RSC (C), DVT (D), and POS2 (E). In each panel, the location of the relevant brain area is indicated in red on the brain map (top); a 3D-rendered representation of the bilateral group-level hippocampus mask (middle; transparent grey) is presented overlaid with the endpoint density map associated with each brain area (green); representative slices of the head, body, and tail of the hippocampus are displayed in the coronal plane (bottom; grey) and overlaid with endpoint density maps (white). Note that the spatial distribution of endpoint density within the hippocampus associated with each of these medial parietal brain areas is primarily localised to the posterior medial hippocampus (yellow arrows in panels A–E). ProS and POS1 also display clusters of endpoint density in a circumscribed region in the anterior medial hippocampus (white arrows in panels A and B). A, anterior; P, posterior; M, medial; L, lateral.
Figure 2—figure supplement 3.
Figure 2—figure supplement 3.. Representative examples of the spatial distribution of endpoint density within the hippocampus associated with the five most highly connected non-medial temporal lobe (non-MTL) temporal brain areas.
Representative examples of the location of endpoint densities associated with TF (A), Gd (B), TGv (C), TE2a (D), and TE2p (E). In each panel, the location of the relevant brain area is indicated in red on the brain map (top); a 3D-rendered representation of the bilateral group-level hippocampus mask (middle; transparent grey) is presented overlaid with the endpoint density map associated with each brain area (green); representative slices of the head, body, and tail of the hippocampus are displayed in the coronal plane (bottom; grey) and overlaid with endpoint density maps (white). Note that the spatial distribution of endpoint density within the hippocampus associated with each of these temporal brain areas is primarily localised to portions of the lateral hippocampal head and body (blue arrows in panels A–E) and a circumscribed region in the anterior medial hippocampus (white arrows in panels A–D). A, anterior; P, posterior; M, medial; L, lateral.
Figure 2—figure supplement 4.
Figure 2—figure supplement 4.. Representative examples of the spatial distribution of endpoint density within the hippocampus associated with the five most highly connected occipital brain areas.
Representative examples of the location of endpoint densities associated with V1 (A), V2 (B), V3 (C), V4 (D), and V6 (E). In each panel, the location of the relevant brain area is indicated in red on the brain map (top); a 3D- rendered representation of the bilateral group-level hippocampus mask (middle; transparent grey) is presented overlaid with the endpoint density map associated with each brain area (green); representative slices of the head, body, and tail of the hippocampus are displayed in the coronal plane (bottom; grey) and overlaid with endpoint density maps (white). Note that the spatial distribution of endpoint density within the hippocampus associated with each of these occipital brain areas is primarily localised to the posterior medial hippocampus (yellow arrows in panels A–E). V1 and V2 also display clusters of endpoint density in a circumscribed region in the anterior medial hippocampus (white arrows in panels A and B). A, anterior; P, posterior; M, medial; L, lateral.
Figure 3.
Figure 3.. Averaged endpoint density maps for anatomically related brain areas.
We averaged the endpoint density maps for the mostly highly connected brain areas in temporal (A; TF, TGd, TGv, TE2a, TE2p), medial parietal (B; ProS, POS1, RSC, DVT, POS2), and occipital (C; V1–4, V6, V3a) cortices and each of these regions combined (D). In each panel, the location of the relevant brain areas are indicated in red on the brain map (left); a 3D-rendered representation of the bilateral group-level hippocampus mask is presented (middle; transparent grey) overlaid with the endpoint density map associated with each collection of brain areas; representative slices of the head, body, and tail of the hippocampus are displayed in the coronal plane (right; grey) and overlaid with endpoint density maps (white). Average endpoint density associated with temporal areas (A) was primarily localised along the anterior lateral hippocampus and a circumscribed region in the anterior medial hippocampus (blue and white arrows, respectively). Average endpoint density associated with medial parietal (B) and occipital (C) areas was primarily localised to the posterior medial hippocampus (yellow arrows) and, to a lesser degree, circumscribed regions in the anterior medial hippocampus (white arrows). Average endpoint density associated with these temporal, medial parietal, and occipital brain areas combined (D) was localised to circumscribed regions in the posterior and anterior medial hippocampus (yellow and white arrows, respectively) and in punctate clusters along the anterior–posterior extent of the lateral hippocampus (blue arrows), suggesting that these specific regions within the hippocampus are highly connected with multiple cortical areas. A, anterior; P, posterior; M, medial; L, lateral.
Figure 4.
Figure 4.. Representative examples of single-subject analysis.
(A) 3D rendering of the hippocampus tractogram for a single participant showing isolated tracks with an endpoint in the hippocampus viewed in the sagittal plane (displayed with transparency; high intensity represents high density of tracks). (B) 3D-rendered left hippocampus masks (transparent grey) for the same participant overlaid with isolated streamlines associated with the left hemisphere areas TF (red) and V1 (turquoise). The location of areas TF and V1 is indicated on the brain maps (top). (C) 3D-rendered bilateral hippocampus mask for the same participant (transparent grey) overlaid with isolated streamlines and endpoint density maps associated with the left hemisphere areas TF (red) and V1 (turquoise). Note that, while streamlines associated with areas TF and V1 are primarily ipsilateral in nature, streamlines associated with V1 also project to the contralateral hippocampus. (D) 3D-rendered left hippocampus masks (transparent grey) for the same participant overlaid with endpoint density maps associated with areas TF (red) and V1 (turquoise). For TF and V1, we present a coronal section of the T1-weighted structural image overlaid with the endpoint density maps and a corresponding slice of postmortem hippocampal tissue (from a different subject) for anatomical comparison (bottom). For both TF (red border; level of the uncal apex) and V1 (turquoise border; level of the hippocampal tail), endpoint density is primarily localised to a circumscribed region in the medial hippocampus aligning with the location of the distal subiculum/proximal presubiculum (black arrows; also see Figure 5A). A, anterior; P, posterior; M, medial; L, lateral.
Figure 4—figure supplement 1.
Figure 4—figure supplement 1.. Cortical areas display both overlapping and spatially unique endpoints within specific regions of the hippocampus.
Group-level analysis revealed that specific cortical areas (e.g. V1 and V2) showed preferential connectivity with overlapping regions within the hippocampus (e.g. within the posterior medial hippocampus; see Figure 2—figure supplement 4 for an example). However, at the single-participant level, individual endpoints associated with each of these areas display both overlapping and spatially unique patterns (compare the spatial distribution of streamline endpoints associated with V1 [cyan] and V2 [red] in the posterior medial hippocampus). This suggests that, while different cortical areas display overlapping patterns of connectivity within specific regions of the hippocampus, subtle differences in how each cortical region connects within these areas of overlap likely exist.
Figure 5.
Figure 5.. Anatomical location of endpoint densities within the hippocampus and comparison with results of non-human primate studies.
(A) Representative slices of the head (left), body (middle), and tail (right) of the hippocampus displayed in the coronal plane (grey) and overlaid with group-level endpoint density maps associated with areas TF (head and body; white) and V1 (tail; white). Schematic representations of roughly equivalent slices of the hippocampus showing hippocampal subfields are displayed below each slice. Schematic representations were taken from the Allen Adult Human Brain Atlas website (https://atlas.brain-map.org/; Ding et al., 2016; Allen Institute for Brain Science, 2004). The vestigial hippocampal sulcus (black line) is overlaid on the hippocampus masks and schematic diagrams to aid comparison. Note that the endpoint density in the lateral hippocampus (blue ellipsoids) aligns with the location of the distal CA1/proximal subiculum. Endpoint density in the medial hippocampus (brown ellipsoids) aligns with the location of distal subiculum/proximal presubiculum. (B–D) 3D-rendered representations of the group-level hippocampus mask (left; transparent grey) are overlaid with endpoint density maps (green) associated with RSC (B), PeEc (C), and TE2a (D). Schematic representations of the macaque hippocampus (right; images reproduced with permission from Insausti and Muñoz, 2001) show the location of labelled cells following retrograde tracer injection into the RSC (B; red), PeEc (C; black points), and TE2a (D; black points) (Insausti and Muñoz, 2001). The right panel of (C) and (D) displays slices of the macaque hippocampus in the coronal plane displaying the location of labelled cells (black points) and roughly equivalent slices of human hippocampus in the coronal plane (grey) overlaid with endpoint density maps (white). Note that labelled cells and endpoint density in the macaque and human respectively are localised to similar regions along the anterior–posterior and medial (brown ellipsoids) – lateral (blue ellipsoids) axes of the hippocampus. However, areas of difference also exist (D; red ellipsoid). M, medial; L, lateral; A, anterior; P, posterior.
Figure 6.
Figure 6.. The location of the anterior medial anatomical cluster aligns with the location of a commonly observed anterior medial functional cluster.
(A) A 3D-rendered representation of the bilateral group-level hippocampus mask (top; transparent grey) is presented overlaid with the endpoint density map averaged across the most highly connected brain areas in temporal, medial parietal, and occipital cortices (green; see Figure 3D for details); a representative slice of hippocampus in the coronal plane (bottom panel; grey) at the level of the uncal apex (indicated by white line) is presented overlaid with the endpoint density map (white). (B) An axial section of a T2-weighted image (top; from a separate study) showing the bilateral hippocampus overlaid with the location of a circumscribed functional cluster observed in the anterior medial hippocampus during a functional MRI investigation of visuospatial mental imagery, reproduced from Figure 2b from Dalton et al., 2018. A representative slice of the hippocampus (bottom-left panel; red border) at the level of the uncal apex (indicated by red line) is presented to show the location of this anterior medial functional cluster in the coronal plane, reproduced from Figure 3a from Dalton et al., 2018. Circumscribed functional clusters in the anterior medial hippocampus are commonly observed in studies of ‘scene-based visuospatial cognition’ such as episodic memory, prospection and scene perception (bottom-right panel; orange border). Left image was reproduced from Figure 3 from Zeidman et al., 2015b. Middle image was reproduced from Figure 3 from Addis et al., 2012. Right image was reproduced from Figure 4a from Lee et al., 2013. Note that the location of these commonly observed functional clusters in the anterior medial hippocampus (black arrows in panel B) aligns with the location of the anatomical cluster in the anterior medial hippocampus observed in this study (white arrows in panel A). M, medial; L, lateral.
Figure 7.
Figure 7.. Comparison of automated and manual hippocampus segmentations.
Representative examples of the automated hippocampus mask derived from the Human Connectome Project Multi-Modal Parcellation (HCPMMP) and the manually segmented hippocampus mask. We display examples from anterior (A) to posterior (D) portions of the hippocampal head. In each panel, we present a coronal slice of the T1-weighted image focused on the right temporal lobe for a single participant (left; hippocampus indicated by *), the same image overlaid with the automated hippocampus mask derived from the HCPMMP (middle; white) and the same image overlaid with both the automated HCPMMP hippocampus mask (right; white) and the manually segmented hippocampus mask (transparent red). Note that in the anterior-most slices (A, B) the automated mask does not cover the entire extent of the hippocampus (indicated by red arrows) and in more posterior slices (C, D) the automated mask often overextends across the lateral ventricle superior to the hippocampus and into the adjacent white matter (indicated by black arrows). Streamlines making contact with these erroneous portions of the automated hippocampus mask may lead to results that are biologically implausible.
Figure 7—figure supplement 1.
Figure 7—figure supplement 1.. Adjustment of grey matter–white matter interface (gmwmi) underlying the hippocampus.
(A) T1-weighted structural MRI scan showing the right medial temporal lobe (left; hippocampus indicated by *) in the coronal plane for a single participant and the manually segmented hippocampus mask (red) overlaid on the T1-weighted image (right). (B) Left: the gmwmi (white line) showing the right medial temporal lobe in the coronal plane; middle: the manually segmented hippocampus mask (red) overlaid on the gmwmi. Note: portions of detected gmwmi immediately inferior to the hippocampus lie outside of the hippocampus mask (indicated by red arrow). If left unchanged, the anatomically informed tractography algorithm used in this study would terminate tracks as they reach this band, thus creating an erroneous band of track endpoints in this region, introducing misleading results. Right: the hippocampus mask (transparent red) and extended hippocampus mask (blue) overlaid on the gmwmi. Note: the extended hippocampus mask encompasses the gmwmi immediately inferior to the hippocampus. This allows streamlines to enter/leave the hippocampus here rather than terminate at the gmwmi (see ‘Materials and methods’ for detail).
Figure 7—figure supplement 2.
Figure 7—figure supplement 2.. Analysis pipeline.
(A) Block diagram of the workflow. Green blocks indicate procedures that involved manual segmentation, red blocks indicate connectivity vectors/matrices from which connectivity measurements were obtained, and blue blocks indicate intermediate images. (B) Sagittal view of ‘modified 5TT’ image containing the manually segmented hippocampus labelled as ‘5th tissue type’ (i.e. no anatomical prior for tracking) shown in white. (C) Sagittal view of modified parcellation image containing the whole-hippocampus mask (shown in orange). (D) Sagittal view of modified parcellation image containing the regional hippocampus masks (head, body, and tail shown in yellow, red, and blue, respectively).
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